Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity

Abstract

The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.

The invention claimed is: 
     
       1. A compound of Formula (A), or a pharmaceutically acceptable salt or deuterated derivative thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R is chosen from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched C 1-4  alkyl group, a linear or branched C 1-4  hydroxyalkyl group, and a linear or branched C 1-4  alkoxy group, 
 n is lor 2, 
 R 1  is: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 R 2  and R 3  are independently chosen from a hydrogen atom, a linear or branched C 1-4  alkyl group, a (C 5-6  aryl)-(C 1-4 )alkyl group, and a linear or branched C 1-4  alkoxy group, 
 R′ is chosen from a hydrogen atom or a linear or branched C 1-4  alkyl group, 
 * is a point of attachment of R 1  to the remainder of the molecule of Formula (A), 
 L x  is a suitable covalent linker, and 
 B represents a group of Formula (IB): 
 
       
       
         
           
           
               
               
           
         
         wherein:
 R 4  is chosen from the group consisting of a hydrogen atom, a linear or branched C 1-4  alkyl group, and a linear or branched C 1-4  alkoxy group, 
 Ar is chosen from the group consisting of a C 3-10  saturated or unsaturated, mono- or bicyclic cycloalkyl group; a C 5 -C 14  mono- or bicyclic aryl group; a 3 to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms chosen from N, S, and O; and a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O; and wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, a nitro group, an oxo group, a carboxy group, a C 1-4  alkyl group, a C 1-4  alkoxy group, —CF 3 , —OCF 3 , —NR e R f , —(CH 2 ) p —OH, —NR e (CO)R f , —NR e —SO 2 —R g , —SO 2 NR e R f , —OC(O)R h , and —NR e (CH 2 ) (0-2) —R i , wherein p is 0, 1 or 2 and wherein: 
 
         R e  and R f  are independently chosen from a hydrogen atom and a linear or branched C 1-4  alkyl group,
 R g  is chosen from the group consisting of a linear or branched C 1-4  alkyl group, a C 5-6  aryl group, and a saturated or unsaturated C 3-8  cycloalkyl, wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group, and a C 1-4  alkoxy group, R h  is chosen from a hydrogen atom, —NR e R f , and a C 5-6  aryl group, which is optionally substituted with one or more substituents chosen from a C 1-4  alkyl group and a C 1-4  alkoxy group, 
 R i  is chosen from the group consisting of a C 5-6  aryl group, a C 3-8  cycloalkyl group, and a 3 to 8 membered saturated or unsaturated heterocyclyl group, which groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group, and a C 1-4  alkoxy group. 
 
       
     
     
       2. The compound according to  claim 1 , wherein L x  is Formula (La) or Formula (Lb): 
       
         
           
           
               
               
           
         
         wherein k1, k2, s1, s2, l2, t1, and t2 are independently 0 or 1;
 A 1 , A 2 , A 3 , A 4  and A 5  are independently chosen from the group consisting of a direct bond, a C 1-10  alkylene group, a C 2-10  alkenylene group, and a C 2-10  alkynylene group, wherein said groups are optionally substituted with one or more substituents chosen from a halogen atom, a hydroxy group, a linear or branched C 1-4  alkyl group, a linear or branched C 1-4  alkoxy group, a C 5-6  aryl group, and a C 3-7  cycloalkyl group, 
 L, L 1  and L 2  are independently chosen from a direct bond, —O—, —NR c —, —S—, —S(O)—, —SO 2 —, —NR c (CO)—, —(CO)NR c —, —NR c (CO)(CH 2 ) q O—, —O(CH 2 ) q (CO)NR c —, —NR c (CO)(CH 2 ) q NR c (CO)—, —O(CH 2 ) q NR c —, —NR c (CH 2 ) q O—, —NR c (CO)NR d —, —C(O)—, —C(O)O—, —OC(O)—, —S(O) 2 NR c —, —NR c S(O) 2 —, —NR c S(O) 2 NR d —, —C(O)NR c S(O) 2 —, and —S(O) 2 NR c C(O)—, wherein R c  and R d  are independently chosen from a hydrogen atom and a linear or branched C 1-4  alkyl group and q is 0, 1, 2, 3 or 4, 
 G and G 2  are independently chosen from the group consisting of a direct bond; a C 3-10  mono- or bicyclic cycloalkyl group; a C 5 -C 14  mono- or bicyclic aryl group; a 3 to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms chosen from N, S, and O; a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O; and a bicyclic ring system comprising two monocyclic ring systems which are linked between each other by a covalent bond or by a —O— or —NH— group; wherein said monocyclic ring systems are independently chosen from a C cydcloalkyl group; a C 5-6  aryl group; a 3 to 8-membered saturated or unsaturated heterocyclyl group having one or more heteroatoms chosen from N, S, and O; and a 5- to 6-membered heteroaryl group having one or more heteroatoms chosen from N, S, and O; wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a carboxy group, a cyano group, a nitro group, a hydroxy group, an oxo group, a trifluoromethyl group, and a trifluoromethoxy group. 
 
       
     
     
       3. The compound according to  claim 2 , wherein k1, k2, s1, s2, l2, t1 and t2 are 0. 
     
     
       4. The compound according to  claim 3 , wherein Lx is Formula (Lb1): 
       
         
           
           
               
               
           
         
       
     
     
       5. The compound according to  claim 1 , wherein Lx is -A 1 -G-L-A 2 -. 
     
     
       6. The compound according to  claim 1 , wherein Ar is formula (a), (b), (c), or (d): 
       
         
           
           
               
               
           
         
         wherein
 G a  and G b  are independently chosen from a nitrogen atom and a carbon atom, 
 r is 0, 1, 2 or 3 and 
 R a  is chosen from the group consisting of a halogen atom, an amino group, a cyano group, a nitro group, an oxo group, a carboxy group, a C 1-4  alkyl group, a C 1-4  alkoxy group, —CF 3 , —OCF 3 , —(CH 2 ) p —OH, —NH(CO)H, —NH—SO 2 —R g , —SO 2 NH 2 , —OC(O)H, —O(CO)-(4-methyl)phenyl, —O(CO)—N(CH 3 ) 2 , —OC(O)NH 2 , or —NH(CH 2 ) (1-2) —R i , wherein p is as defined above and R g  and R i  are independently chosen from a phenyl group optionally substituted with a one substituent chosen from a methyl group and a methoxy group, 
 R j  is a halogen atom, 
 T is chosen from the group consisting of —CH 2 — and —NH—, 
 Both X and Y are a hydrogen atom or X together with Y forms —CH 2 —CH 2 —, —CH═CH—, —CH 2 —O—, or —S—, wherein in the case of —CH 2 —O— the methylene group is bound to the carbonyl group holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y. 
 
       
     
     
       7. The compound according to  claim 6 , wherein Ar is formula (a) or (b) wherein: 
       
         
           
           
               
               
           
         
         Both G a  and G b  are a carbon atom, 
         R a  is chosen from the group consisting of halogen atom, amino group, cyano group, nitro group, —(CH 2 ) p —OH, —NH(CO)H, —NH—SO 2 —CH 3 , —SO 2 NH 2 , —OC(O)H, —O(CO)-(4-methyl)phenyl, —O(CO)—N(CH 3 ) 2 , —OC(O)NH 2 , or —CF 3 , wherein p is 0, 1 or 2, 
         T is —NH—, 
         Both X and Y are a hydrogen atom or X together with Y forms —CH═CH—, —CH 2 —CH 2 —, —CH 2 —O—, or —S—, wherein in the case of —CH 2 —O— the methylene group is bound to the carbon atom in the amido substituent holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y. 
       
     
     
       8. The compound according to  claim 6  or  7 , wherein Ar is chosen from the group consisting of 3-bromoisoxazol-5-yl, 3,4-dihydroxyphenyl, 4-hydroxy-3-(methylsulfonamido)phenyl, 3,4-bis(4-methylbenzoyloxy)phenyl, 3,5-bis(dimethylcarbamoyloxy)phenyl, (5-hydroxy-6-hydroxymethyl)pyrid-2-yl, (4-amino-3,5-dichloro)phenyl, 4-hydroxyphenyl, 4-hydroxy-3-(2-hydroxyethyl)phenyl, 4-hydroxy-3-(hydroxymethyl)phenyl, [4-amino-3-chloro-5-(trifluoromethyl)]phenyl, (3-formamido-4-hydroxy)phenyl, 8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl, 8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl, 5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, or 4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl. 
     
     
       9. The compound according to  claim 7 , wherein Ar is the compound of formula (b) wherein T is —NH. 
     
     
       10. The compound according to  claim 1 , wherein Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 R is chosen from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched C 1-4  alkyl group, a linear or branched C 1-4  hydroxyalkyl group, and a linear or branched C 1-4  alkoxy group, 
 n is 1 or 2, 
 X and Y are both a hydrogen atom or X together with Y forms —CH═CH—, —CH 2 —O—, or —S—, wherein in the case of —CH 2 —O— the methylene group is bound to the carbon atom in the amido substituent holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y, 
 A 1  and A 2  are independently chosen from the group consisting of a direct bond, a C 1-10  alkylene group, a C 2-10  alkenylene group, and a C 2-10  alkynylene group, wherein said groups are optionally substituted with one or more substituents chosen from a halogen atom, a hydroxy group, a linear or branched C 1-4  alkyl group, a linear or branched a C 1-4  alkoxy group, a C 5-6  aryl group, and a C 3-7  cycloalkyl group, 
 G is chosen from the group consisting of a direct bond; a C 3-10  mono- or bicyclic cycloalkyl group; a C 5-14  mono- or bicyclic aryl group; a 3- to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms chosen from N, S, and O; a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O; and a bicyclic ring system consisting of two monocyclic ring systems which are linked between each other by a covalent bond or by a —O— group, wherein said monocyclic ring systems are independently chosen from a C 3-8  cycloalkyl group; a C 5-6  aryl group; a 3- to 8-membered saturated or unsaturated heterocyclyl group having one or more heteroatoms chosen from N, S, and O; and a 5- to 6-membered heteroaryl group having one or more heteroatoms chosen from N, S, and O; wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a carboxy, group, a cyano group, a nitro group, a hydroxy group, an oxo group, a trifluoromethyl group, and a trifluoromethoxy group, 
 L is chosen from a direct bond, —O—, —NR c —, —S—, —S(O)—, —SO 2 —, —NR c (CO)—, —(CO)NR c —, —NR c (CO)(CH 2 ) q O—, —O(CH 2 ) q (CO)NR c —, —NR c (CO)(CH 2 ) q NR c (CO)—, —O(CH 2 ) q NR c —, —NR c (CH 2 ) q O—, —NR c (CO)NR d —, —C(O)—, —C(O)O—, —OC(O)—, —S(O) 2 NR c —, —NR c S(O) 2 —, —NR c S(O) 2 NR d —, —C(O)NR c S(O) 2 —, or —S(O) 2 NR c C(O)—, wherein R c  and R d  are independently chosen from a hydrogen atom and a linear or branched C 1-4  alkyl group and q is 0, 1, 2, 3 or 4, 
 R 1  is: 
 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 2  and R 3  are independently chosen from a hydrogen atom, a linear or branched C 1-4  alkyl group, and a (C 5-6  aryl)-(C 1-4 ) alkyl group and R′ is chosen from a hydrogen atom and a linear or branched C 1-4  alkyl group. 
       
     
     
       11. The compound according to  claim 1 , wherein A 1  and A 2  are independently chosen from the group consisting of C 1-6  alkylene group, C 1-6  alkenylene group, and C 1-6 alkynylene group, wherein said groups are optionally substituted with one or more substituents chosen from a halogen atom, a hydroxy group, a C 1-2  alkyl group, a C 1-2  alkoxy group, a C 5-6  aryl group, and a C 3-6  cycloalkyl group. 
     
     
       12. The compound according to  claim 1 , wherein X together with Y forms —CH═CH— or —CH 2 —O—. 
     
     
       13. The compound according to  claim 1 , wherein L is chosen from the group consisting of a direct bond, —O—, —NR c —, —S—, —S(O)—, —SO 2 —, —NR c (CO)—, —(CO)NR c —, —NR c (CO)(CH 2 ) q O—, —O(CH 2 ) q (CO)NR c —, —NR c (CO)(CH 2 ) q NR c (CO)—, —O(CH 2 ) q NR c —, —NR c (CH 2 ) q O—, —NR c (CO)NR d —, —C(O)—, —C(O)O—, —OC(O)—, —S(O) 2 NR c —, —NR c S(O) 2 —, —NR c S(O) 2 NR d —, —C(O)NR c S(O) 2 —, or —S(O) 2 NR c C(O)—, wherein R c  and R d  are independently chosen from a hydrogen atom and a linear or branched C 1-4  alkyl group and q has a value of 0, 1, 2, 3 or 4. 
     
     
       14. The compound according to  claim 13 , wherein L is chosen from a direct bond, —NR c (CO)—, —(CO)NR c —, —O(CH 2 ) q (CO)NR c — or —C(O)—. 
     
     
       15. The compound according to  claim 1 , wherein G is chosen from the group consisting of a direct bond; a C 3-7  cycloalkyl group; a C 5-14  mono- or bicyclic aryl group; a 3- to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms selected from N, S, and O; a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O; or a bicyclic ring system comprising two monocyclic ring systems which are linked between each other by a covalent bond or by a —O— group, wherein said monocyclic ring system are independently chosen from the group consisting of a C 3-8  cycloalkyl group and a C 5-6  aryl group, wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a carboxy group, a cyano group, a nitro group, a hydroxy group, an oxo group, a trifluoromethyl group, and a trifluoromethoxy group. 
     
     
       16. The compound according to  claim 15 , wherein, G is chosen from the group consisting of a C 3-7  cycloalkyl group, a C 5 -C 6  aryl group, or a group of Formula (Iwa): 
       
         
           
           
               
               
           
         
         wherein
 V, W and Z are independently chosen from —N—, —NH—, —C—, —CH—, —S—, —O—, and —C(O)—, 
 
         wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group and a C 1-4  alkoxy group. 
       
     
     
       17. The compound according to  claim 16 , wherein W is chosen from —N—, —NH—, or a —C(O)— group. 
     
     
       18. The compound according to  claim 16 , wherein V is chosen from —N—, —NH—, —S—, or —O—. 
     
     
       19. The compound according to  claim 16 , wherein G is chosen from a phenylene group, a cyclohexyl group, or a group of Formula (Iwb): 
       
         
           
           
               
               
           
         
         wherein V is chosen from —N—, —NH—, or —O— and W is a —C(O)— group, and wherein the cyclic groups are independently optionally substituted with one or two substituents chosen from a chlorine atom, methyl group, and methoxy group. 
       
     
     
       20. The compound according to  claim 1 , wherein R 1  is formula: 
       
         
           
           
               
               
           
         
         wherein R′, R 2  and R 3  are independently chosen from a hydrogen atom and a C 1-2  alkyl group. 
       
     
     
       21. A compound according to  claim 20 , wherein R 1  is formula: 
       
         
           
           
               
               
           
         
       
     
     
       22. The compound according to  claim 1 , wherein R is chosen from the group consisting of a hydrogen atom, a halogen atom, or a hydroxy group. 
     
     
       23. The compound according to  claim 1 , wherein n is 1 or 2. 
     
     
       24. The compound according to  claim 1 , wherein A 1  and A 2  independently are a C 1-4  alkylene group optionally substituted with one or two methyl groups, X together with Y forms —CH═CH—, L is chosen from the group consisting of a direct bond, —NR c (CO)—, or —(CO)NR c —, wherein R c  is chosen from a hydrogen atom and a methyl group, G is chosen from a phenylene group, a cyclohexyl group, or a group of Formula (Iwb): 
       
         
           
           
               
               
           
         
         wherein V is chosen from —N—, —NH—, or —O— and W is a —C(O) group, and wherein the cyclic groups are independently optionally substituted with one or two substituents chosen from a chlorine atom, a methyl group, and a methoxy group, and R 1  has formula: 
       
       
         
           
           
               
               
           
         
         wherein both R 2  and R 3  are a hydrogen atom and R′ is chosen from a hydrogen atom or a methyl group, R is a hydrogen atom and n is 1. 
       
     
     
       25. The compound according to  claim 1 , having Formula (I): 
       
         
           
           
               
               
           
         
         wherein, R is a hydrogen atom and n is 1, A 1  and A 2  are independently chosen from a direct bond and a C 1-6  alkylene group optionally substituted with a methyl group, X together with Y forms —CH═CH—, —CH 2 —CH 2 — or —CH 2 —O—, L is chosen from the group consisting of a direct bond, —O—, —NR c (CO)O—, —O(CH 2 )(CO)NR c —, —NR c (CO)— —(CH 2 ) 4 NR c (CO)—, —(CH 2 ) (0-1) NR c (CO)—, —(CO)NR c —, or —NH(CO)NH—, wherein R c  is chosen from a hydrogen atom or a methyl group, G is chosen from a direct bond, a phenylene group, a pyridyl group, a cyclobutyl group, a cyclohexyl group, or a group of Formula (Iwa): 
       
       
         
           
           
               
               
           
         
         wherein V and Z independently are chosen from the group consisting of —N—, —NH—, —C—, —O—, and —S—, and W is chosen from —N—, —NH—, —C—, and a —C(O)— group, and wherein the phenylene group, pyridyl group, cyclobutyl group, cyclohexyl group, and the group of Formula (Iwa) are independently optionally substituted with one or two substituents chosen from a chlorine atom, methyl group, and methoxy group, R 1  has formula: 
       
       
         
           
           
               
               
           
         
         wherein both R 2  and R 3  are independently chosen from a hydrogen atom, a methyl group, a hexyl group, and a propyl group substituted with a phenyl group and R′ is a hydrogen atom or a methyl group. 
       
     
     
       26. The compound according to  claim 1 , wherein the compound is chosen from:
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenoxy]butyl}biphenyl-2-yl)carbamate 
 trans-4-(methylamino)cyclohexyl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol-1-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol-1-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-indol-1-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol-1-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[3-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenoxy]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenoxy]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{4-[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenoxy]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)ethyl]amino}methyl)-1,3-benzoxazol-2-yl]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[3-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-ethyl]amino}ethyl)phenoxy]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[({[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}carbonyl)oxy]-propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl-1H-indol-1-yl]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzothiazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenoxy]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1,3-benzoxazol-2-y]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2H-1,2,3-benzotriazol-2-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{4-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(5-{4-[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenoxy]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(5-{4-[6-({[(2R)-2-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[4-({[(2R)-2-hydroxy-2-(8-hyroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]propyl}biphenyl-2-y)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[6-({[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]propyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-indol-1-yl]butyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{4-[6-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{5-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]pentyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{3-[6-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]propyl}biphenyl-2-yl)carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl(4-{5-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]pentyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl {4-[(6-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}hexyl)oxy]biphenyl-2-yl}carbamate, 
 trans-4-aminocyclohexyl(5-{4-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol-1-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl[5-(4-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(5-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}5-oxopentyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(4-({[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl(4-{4-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-[methyl(3-phenylpropyl)amino]cyclohexyl[4-(4-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(3-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-3-oxopropyl)biphenyl-2-yl]carbamate, 
 (3R)-1-azabicyclo[2.2.2]oct-3-yl[4-(4-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl(4-{4-[[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl](methyl)amino]-4-oxobutyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl[4-(4-(4-{[trans-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)cyclohexyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}propyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl(4-{4-[(5-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-5-oxopentyl)(methyl)amino]-4-oxobutyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{3-[{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenoxy]acetyl}(methyl)amino]-propyl}biphenyl-2-yl)carbamate, 
 trans-4-amino-1-methylcyclohexyl[4-(3-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-3-oxopropyl)biphenyl-2-yl]carbamate, 
 trans-4-amino-1-methylcyclohexyl[4-(3-{[trans-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)cyclohexyl]amino}-3-oxopropyl)biphenyl-2-yl]carbamate, 
 1-azabicyclo[2.2.2]oct-4-yl[4-(3-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-3-oxopropyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl(4-{2-[{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenoxy]acetyl}(methyl)amino]ethyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{2-[({[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}carbonyl)oxy]ethyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{4-[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenoxy]butyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[trans-3-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)cyclobutyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(3-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxybenzoyl]amino}propyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(3-{4-[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenoxy]phenyl}propyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)benzyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)pyridin-2-yl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-[hexyl(methyl)amino]cyclohexyl[4-(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)pyridin-3-yl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 Trans-4-aminocyclohexyl(4-(3-(Trans-4-((((2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)cyclohexanecarboxamido)propyl)-biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl(4-{3-[({[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}carbonyl)amino]propyl}biphenyl-2-yl)carbamate, 
 trans-4-aminocyclohexyl[4-(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxybenzoyl]amino}butyl)biphenyl-2-yl]carbamate, 
 1-azabicyclo[2.2.2]oct-4-yl[4-(4-{[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 trans-4-aminocyclohexyl(4-{3-[({[trans-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)cyclohexyl]oxy}acetyl)methyl)amino]propyl}biphenyl-2-yl)carbamate, 
 1-azabicyclo[2.2.2]oct-4-yl[4-(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate 
 trans-4-aminocyclohexyl(4-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-benzimidazol-1-yl]butyl}biphenyl-2-yl)carbamate, 
 trans-4-amino-1-methylcyclohexyl[4-(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 1-azabicyclo[2.2.2]oct-4-yl(4-{3-[{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenoxy]acetyl}(methyl)amino propyl}biphenyl-2-yl)carbamate, 
 1-azabicyclo[2.2.2]oct-4-yl[4-(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxybenzoyl]amino}butyl)biphenyl-2-yl]carbamate and 
 1-azabicyclo[2.2.2]oct-4-yl[4-(4-{[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)pyridin-3-yl]amino}-4-oxobutyl)biphenyl-2-yl]carbamate, 
 
       or pharmaceutically acceptable salts or deuterated derivates thereof. 
     
     
       27. A pharmaceutical composition comprising the compound according to  claim 1  and a pharmaceutically acceptable diluent or carrier. 
     
     
       28. A combination product comprising (i) the compound according to  claim 1 ; and (ii) at least one additional compound chosen from a corticosteroid and a PDE4 inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal body. 
     
     
       29. The compound according to  claim 8 , wherein Ar is chosen from the group consisting of 4-hydroxy-3-(hydroxymethyl)phenyl, (3-formamido-4-hydroxy)phenyl, 8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl, 8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl, or 5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl. 
     
     
       30. The compound according to  claim 11 , wherein A 1  and A 2  independently are a C 1-6  alkylene group optionally substituted with one or more substituents selected from a C 1-2  alkyl group, a C 1-2  alkoxy group, and a phenyl group. 
     
     
       31. The compound according to  claim 30 , wherein A 1  and A 2  independently are a C 1-4  alkylene group optionally substituted with one or two substituents selected from a methyl group and a methoxy group. 
     
     
       32. The compound according to  claim 31 , wherein A 1  and A 2  independently are a C 1-4  alkylene group optionally substituted with one or two methyl groups. 
     
     
       33. The compound according to  claim 12 , wherein X together with Y forms —CH═CH—. 
     
     
       34. The compound according to  claim 13 , wherein L is chosen from the group consisting of direct bond, —O—, —NR c —, —NR c (CO)—, —(CO)NR c —, —NR c (CO)(CH 2 ) q O—, —O(CH 2 ) q (CO)NR c —, —NR c (CO)(CH 2 ) q NR c (CO)—, —O(CH 2 ) q NR c —, —NR c (CH 2 ) q O—, —NR c (CO)NR d —, —C(O)—, —C(O)O—, or —OC(O)— wherein R c  and R d  are independently selected from a hydrogen atom and a methyl group and q has a value of 0, 1, 2, 3 or 4. 
     
     
       35. The compound according to  claim 34 , wherein, L is selected from a direct bond, —O—, —NR c (CO)—, —(CO)NR c —, —NR c (CO)(CH 2 ) q O—, —O(CH 2 ) q (CO)NR c — or —C(O)—, wherein R c  and R d  independently are selected from a hydrogen atom and a methyl group and q has a value of 0, 1, 2, 3 or 4. 
     
     
       36. The compound according to  claim 14 , wherein L is chosen from a direct bond, —NR c (CO)— or —(CO)NR c —, wherein R c  is chosen from a hydrogen atom or a methyl group. 
     
     
       37. The compound according to  claim 15 , wherein G is chosen from the group consisting of a direct bond; a C 3-7  cycloalkyl group; a C 5 -C 6  aryl group; a 8- to 10-membered saturated or unsaturated bicyclic heterocyclyl group having one or more heteroatoms selected from N, S, and O; and a 8- to 10-membered bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O, wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a cyano group, a nitro group, a hydroxy group and an oxo group. 
     
     
       38. The compound according to  claim 17 , wherein W is a —C(O)— group. 
     
     
       39. The compound according to  claim 18 , wherein V is chosen from —N—, —NH—, or —O. 
     
     
       40. The compound according to  claim 16 , wherein W is a —C(O)— group and Z is a —N— or —NH— group. 
     
     
       41. A compound accordingly to  claim 21 , wherein R′, R 2  and R 3  are independently chosen from a hydrogen atom and a methyl group. 
     
     
       42. A compound accordingly to  claim 41 , wherein R 2  and R 3  are a hydrogen atom and R′ is a hydrogen atom or a methyl group. 
     
     
       43. The compound according to  claim 22 , wherein R is chosen from a hydrogen atom or a hydroxy group. 
     
     
       44. The compound according to  claim 43 , wherein R is a hydrogen atom. 
     
     
       45. The compound according to  claim 23 , wherein n is 1. 
     
     
       46. A method for treating a subject afflicted with a pathological condition or disease, wherein the pathological condition or disease is chosen from asthma and/or chronic obstructive pulmonary disease, the method comprising administering to said subject an effective amount of a compound according to  claim 1 .